Active pharmaceutical ingredients (APIs) can be prepared in a variety of different forms, for example, chemical derivatives, solvates, hydrates, co-crystals, or salts. APIs may also be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of an API, it is possible to vary the physical properties thereof. For instance, crystalline polymorphs typically have different solubilities such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Polymorphs can also differ in properties such as stability, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical and pharmacological properties thereof.
Poly(ADP-ribose) polymerase (PARP, also called poly(ADP-ribose) synthetase, or PARS) is a nuclear enzyme which catalyzes the synthesis of poly(ADP-ribose) chains from NAD+ in response to single-stranded DNA breaks as part of the DNA repair process (de Murcia, G; de Murcia, J. M. Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem. Sci. 1994, 19,172-176; Alvarez-Gonzalez, R.; Pacheco-Rodriguez, G.; Mendoza-Alvarez, H. Enzymology of ADP-ribose polymer synthesis. Mol. Cell. Biochem. 1994, 138, 33). It has been hypothesized that small molecule inhibitors of PARP may play a potential role in the therapeutic treatment of neurodegenerative disorders, cancers, and other PARP and kinase-related diseases.
A specific PARP inhibitor compound, having the chemical designation 4,5,6,7-tetrahydro-11-methoxy-2-[(4-methyl-1-piperazinyl)methyl]-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione may have utility in the treatment of breast and ovarian tumors and in conjunction with chemotherapy or radiotherapy for the treatment of other drug-resistant cancers. This compound is represented by the following formula (I):
and is referred to hereinafter as “Compound I”. U.S. Pat. No. 7,122,679 and U.S. 2006/0276497 describe Compound I and utility thereof.
Different forms of Compound I can have different melting points, solubilities or rates of dissolution; these physical properties, either alone or in combination, can affect, for example, bioavailability. In light of the potential benefits of alternative forms of APIs, a need exists to identify and prepare alternative forms of Compound I.